Synapses, the sites that allow information to be passed between neurons, are essential for brain function. Their importance is highlighted by the fact that even minor synaptic abnormalities, caused by disease or neurotrauma, result in devastating neurological conditions. Understanding how CNS synapses are targeted, assembled and maintained (or refined) is therefore essential to our understanding of neurological disorders. One set of synapses whose formation and refinement has received considerable attention are those formed between retinal ganglion cells (RGCs), the output neurons of the retina, and target neurons within the brain. Spurred on by Roger Sperry's postulation of the chemoaffinity hypothesis (which postulated that regionalized chemical cues direct topographic mapping of RGC axons within the brain), many groups have searched for and identified chemical/molecular cues necessary for the correct exiting of retinal ganglion cell axons from the retina, the correct crossing of RGC axons at the optic chiasm, the repulsion of RGC axons from non-retinal targets, and the topographic mapping of RGC axons within the lateral geniculate nucleus (LGN) and superior colliculus (SC). Despite these monumental advances, it still remains unclear how different classes of retinal ganglion cells (RGCs) - of which there are more than 22 - target functionally distinct nuclei within the brain. One brain region where class-specific targeting of RGC axons is most evident is the LGN - a thalamic relay nucleus that contains three structurally and functionally distinct subnuclei: the ventral and dorsal LGN (vLGN and dLGN, respectively) and the intergeniculate leaflet that separates them. Since different classes of RGCs target either vLGN and IGL or dLGN, we hypothesized that regionalized guidance cues must exist in the LGN to direct axonal targeting. Preliminary studies have identified several potential guidance cues and have demonstrated that one cue, the extracellular matrix molecule reelin, is necessary for retinogeniculate targeting. The present proposal aims to directly determine whether reelin is necessary for nuclei- and class-specific target of the LGN by RGC axons. Additionally, it proposes to explore both the cellular and molecular mechanisms responsible for reelin-dependent retinogeniculate targeting and to the function consequences of targeting defects that arise in the absence of reelin. Together, the studies proposed here will substantially progress our understanding of retinogeniculate circuit formation and will shed new light on the role of ECM proteins in class-specific targeting of RGC axons. PUBLIC HEALTH RELEVANCE: The establishment of precise connections between neurons in the retina and those in the brain are essential for both image- and non-image-forming functions of the visual system. While it is well documented that different classes of retinal neurons convey image-forming or non-image forming input to central neurons, how axons from each find functionally distinct target nuclei remains unclear. Therefore, the present studies attempt to advance our understanding of visual system circuit formation by searching for molecular cues that guide nuclei- and class-specific targeting of retinal axons.